Two major feedback loops which inhibit ACTH release into blood are known. One is level-sensitive and evident hours after administration of glucocorticoid. This "slow" feedback is tested by the conventional dexamethasone suppression test ("DST"). The second circuit is sensitive to the rate of rise of plasma glucocorticoid concentration, is activated promptly, and so is termed "fast, rate-sensitive". In animals there exist distinct anatomic and pharmacologic substrates for slow versus fast feedback, and human studies have shown disrupted fast feedback in patients with Cushing's disease, but no studies have yet tested the fast feedback circuit in depressed patients. We have recently completed a pilot study to test the novel hypothesis that depressed persons may manifest aberrant rate-sensitive feedback. Of ten endogenously depressed patients and 3 normals, 2 patients and no controls had abnormal DSTs. Two other depressed subjects and no normals had aberrant rate-sensitive ACTH and B-endorphin inhibition determined during precisely metered cortisol infusions. This preliminary data suggests the existence of a previously undescribed abnormality of ACTH secretion in depression, presumably dependent upon pathways distinct from those mediating the DST. We now propose to extend these observations to a larger group of patients and controls, with several goals. First, we wish to define the pattern of ACTH and B-endorphin decline in normals given an infusion of cortisol--a technically difficult question which has never been answered, but for which we now possess appropriate methodology. Second, we wish to examine whether certain depressed patients differ from normals in their fast feedback responses, as our pilot data suggests. Third, we wish to compare the prevalence of fast feedback abnormalities with that of abnormal DST responses in depressed patients. Fourth, we wish to acquire preliminary data as to whether aberrant fast feedback responses in depressives normalize after pharmacotherapy.